US6258947B1 - (3,4,7,8,9,10-hexahydro-6,10-dioxo-6H pyridazino[1,2-A] [1,2] diazepine-1-carboxylic acid derivatives - Google Patents
(3,4,7,8,9,10-hexahydro-6,10-dioxo-6H pyridazino[1,2-A] [1,2] diazepine-1-carboxylic acid derivatives Download PDFInfo
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- US6258947B1 US6258947B1 US09/296,325 US29632599A US6258947B1 US 6258947 B1 US6258947 B1 US 6258947B1 US 29632599 A US29632599 A US 29632599A US 6258947 B1 US6258947 B1 US 6258947B1
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- 0 *OC(=O)C1=CCCN2C(=O)CC[C@H](N)C(=O)N12 Chemical compound *OC(=O)C1=CCCN2C(=O)CC[C@H](N)C(=O)N12 0.000 description 27
- LADMSEDIGCIZCN-UHFFFAOYSA-N CN1C(=O)C2=C(C=CC=C2)C1=O.[H]NC(=O)C1=NC=CC2=C1C=CC=C2 Chemical compound CN1C(=O)C2=C(C=CC=C2)C1=O.[H]NC(=O)C1=NC=CC2=C1C=CC=C2 LADMSEDIGCIZCN-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Definitions
- novel compounds of the invention are compounds of the formula
- R is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the amine is optionally protected.
- R as alkyl are methyl, ethyl, propyl, isopropyl, n-butyl 1 , isobutyl and tert-butyl and as aryl or aralkyl are benzyl and naphthyl.
- Preferred compounds of the invention have the formula
- R 2 is hydrogen and R 1 is selected from the group consisting of
- R a , R b , R c and R d are individually selected from the group consisting of alkyl of 1 to 18 carbon atoms, aryl and aryl of up to 18 carbon atoms and mono- or polycyclic containing at least one heteroatom and X is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R 1 and R 2 together with the nitrogen to which they are attached form a mono- or polycyclic with at least one heteroatom.
- a preferred compound of formula I has the formula
- R is alkyl of 1 to 8 carbon atoms, especially 1,1-dimethylethyl.
- the process of the invention for the preparation of a compound of formula I comprises reacting a compound of the formula
- the starting material has the formula
- R, R 1 and R 2 have the above definitions and the dehydrogenation agent is a strong base, an oxidizing agent or a sulfur or selenium derivative.
- the compounds of formula II are racemic (SR+SS) at the level of the 6-member ring and are novel products. They can be prepared by the following process.
- R is defined as above and the amine is optionally protected comprises reacting a compound of formula I with a reducing agent.
- the resulting compound has the formula
- R, R 1 and R 2 are defined as above and the reducing agent is hydrogen in the presence of Raney nickel, palladium on carbon, palladium dihydroxide in the presence of talc, ruthenium on carbon or rhodium in the presence of aluminum, more preferably hydrogen in the presence of Raney nickel.
- the reaction is effected in the presence of a solvent such as acetic acid, methanol, ethanol, isopropanol, dimethoxyethane, butanone, DMF or acetonitrile.
- the compounds of formula IIIA are intermediates for the preparation of pharmacological products such as the compounds described in EP Patent No. 84,095 and in J. Chem. Soc. Perkin Trans. 1, (1986), p. 1011. Other products of formula II are useful in a similar process.
- Stage A 1-(benzyl) 3-(1,1-dimethylethyl)-2-f1,5-dioxo-2-(1,3-dioxo-14-isoindol-2(3H)-yl-5-benzyloxy-pentyll-tetrahydro-1,3-(2H)-pyridazine dicarboxylate
- a mixture of 4.61 g of the product of Stage A and 47 ml of tetrahydrofuran was mixed at 20° C. and the reaction mixture was hydrogenated at ambient temperature, using 400 mg of palladium on carbon as a catalyst. When the reaction was completed, the reaction mixture was filtered and rinsed with THF to obtain 2.76 g of the desired product.
Abstract
A compound of the formulawherein R is alkyl or aralkyl of up to 18 carbon atoms, the amine function being optionally protected are used to prepare compounds of the formulain which R retains its previous meaning and the amine is optionally protected.
Description
It is an object of the invention to provide the novel compounds of formula I and a process and intermediates for their preparation.
It is another object of the invention to provide the novel compounds of formula III and a process for their preparation.
These and other objects and advantages of the invention will become obvious from the following detailed description.
The novel compounds of the invention are compounds of the formula 
wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the amine is optionally protected.
Examples of R as alkyl are methyl, ethyl, propyl, isopropyl, n-butyl1, isobutyl and tert-butyl and as aryl or aralkyl are benzyl and naphthyl.
Preferred compounds of the invention have the formula 
wherein A is defined as above, R2 is hydrogen and R1 is selected from the group consisting of 
Ra, Rb, Rc and Rd are individually selected from the group consisting of alkyl of 1 to 18 carbon atoms, aryl and aryl of up to 18 carbon atoms and mono- or polycyclic containing at least one heteroatom and X is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R1 and R2 together with the nitrogen to which they are attached form a mono- or polycyclic with at least one heteroatom.
Examples of cyclic protective groups are 
A preferred compound of formula I has the formula 
wherein R is alkyl of 1 to 8 carbon atoms, especially 1,1-dimethylethyl.
The process of the invention for the preparation of a compound of formula I comprises reacting a compound of the formula 
in racemic form at the 6-member ring and R is as defined and above the amine is protected with a dehydrogenation agent to form the corresponding compound of formula I.
Preferably, the starting material has the formula 
wherein R, R1 and R2 have the above definitions and the dehydrogenation agent is a strong base, an oxidizing agent or a sulfur or selenium derivative.
The compounds of formula II are racemic (SR+SS) at the level of the 6-member ring and are novel products. They can be prepared by the following process. 
The starting compounds of the said process are described in or can be prepared as set f orth in J. Chem. Soc. Perkins Trans. 1 (1979), Vol. 6, p. 1451-1454 or J. Chem. Soc. Chem. Comm. (1977), p. 635-36.
The process of the invention for the preparation of a compound of the formula 
wherein R is defined as above and the amine is optionally protected comprises reacting a compound of formula I with a reducing agent.
Preferably, the resulting compound has the formula 
wherein R, R1 and R2 are defined as above and the reducing agent is hydrogen in the presence of Raney nickel, palladium on carbon, palladium dihydroxide in the presence of talc, ruthenium on carbon or rhodium in the presence of aluminum, more preferably hydrogen in the presence of Raney nickel. The reaction is effected in the presence of a solvent such as acetic acid, methanol, ethanol, isopropanol, dimethoxyethane, butanone, DMF or acetonitrile.
The compounds of formula IIIA are intermediates for the preparation of pharmacological products such as the compounds described in EP Patent No. 84,095 and in J. Chem. Soc. Perkin Trans. 1, (1986), p. 1011. Other products of formula II are useful in a similar process.
The products of formula II and IIA in the SR form or the form of a mixture (SR+SS) are novel intermediates as are the compounds of formula III and IIIA with the proviso that R is not hydrogen or tert.-butyl in formula III and in formula IIIA, R is not hydrogen or tert.-butyl when the amine is protected by phthalimido. EP 94,095 describes a compound of formula IIIA when R is tert.-butyl and the amine is phthalimido.
In the following examples, there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.
Preparation a: 1-(benzyl) and 3-(1,1-dimethyl-ethyl) hexahydro-3-(2H)-pyridazinedicarboxylate J. Chem. Soc. Chem. Comm. (1977) p. 635-636 or J. Chem. Soc. Perkin Trans. (1979) Vol 6. p. 1451-1454.
920 μl of BF3-Et2O and a solution of 18.85 g of terbutyl trichloroacetimidate, 45.5 ml of cyclohexane and 57.5 ml of dichloro methane were introduced at 20° C. into a suspension of 11.50 g of 1,2-benzyl hexahydro-1,3(2H) pyridazinedicarboxylate and 115 ml of dichloromethane. After isolation and purification treatment, the expected product was obtained.
Preparation b: benzyl γ-(chlorocarbonyl)-1,3-dioxo-1 H-isoindole-2(3H)-butanoate
30 g of benzyl γ-carboxy-1,3-dioxo-1H-isoindol-(3H)-butanoate (EP 94,095) were introduced, under a nitrogen atmosphere, into 81 ml of terbutylmethylether. The reaction mixture was then cooled to 0°-2° C. and 17 g of phosphorus pentachloride were added. The reaction mixture was allowed to return to ambient temperature and was stirred for 6 hours, concentrated under reduced pressure, taken to 41° C. and the dry extract obtained was entrained using toluene. The product was held at ambient temperature and under a nitrogen atmosphere, then diluted for use in CH2Cl2, to obtain a 0.5 M solution of the desired product.
Stage A: 1-(benzyl) 3-(1,1-dimethylethyl)-2-f1,5-dioxo-2-(1,3-dioxo-14-isoindol-2(3H)-yl-5-benzyloxy-pentyll-tetrahydro-1,3-(2H)-pyridazine dicarboxylate
A 0.5 M solution of 52 ml of the product of Preparation b in, methylene chloride was cooled to 0°-1° C. and 5.6 g of the product of Preparation a and 22 ml of dichloromethane were added thereto. The reaction mixture was stirred for 3 hours at 0°-1° C. and 1.77 ml of pyridine and 11 ml of methylene chloride were added. The dichloromethane was evaporated under reduced pressure at 30° C., followed by taking up in ethyl acetate, washing with aqueous solutions of sodium chloride and sodium bicarbonate. Extraction was carried out with ethyl acetate, followed by drying, rinsing and extracting under reduced pressure to obtain the desired product which was chromatographed on silica and eluting with a heptane-ethyl acetate mixture 60-40 to obtain 4.697 g of the desired product melting at ≦35° C.
Sage B: γ-[[3-[1,1-dimethylethoxy)carbonyl]-tetrahydro-2(1 H)-pyridazinyl]carbonyl]-1,3-dioxo-1H-isoindole-2-(3H)-butanoic acid
A mixture of 4.61 g of the product of Stage A and 47 ml of tetrahydrofuran was mixed at 20° C. and the reaction mixture was hydrogenated at ambient temperature, using 400 mg of palladium on carbon as a catalyst. When the reaction was completed, the reaction mixture was filtered and rinsed with THF to obtain 2.76 g of the desired product.
Stage C: 1,1-dimethylethyl 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino [1,2-a]-1,2-diazepine-1-carboxylate
A solution of 0.846 ml of thionyl chloride in 2.6-ml of dichloromethane was added at 0°+2° C. to a mixture of 2.6 g of the, product of Stage B, 26 ml of methylene chloride and 50 μl of dimethylformamide. The reaction mixture was allowed to return to ambient temperature and was stirred for 6 hours 20 minutes. The isolation and purification operations are carried out to obtain the desired product.
a) Preparation of LDA
7.2 ml of butyllithium were added at about −60° over 10 minutes, under a nitrogen atmosphere with stirring to a mixture of 20 ml of THF and 3.2 ml of diisoopropylamine. The temperature was allowed to rise to 0° C., was held for 1 hour at 0° C. and then was returned to −600° C.
b) Preparation of C6H5SeBr 0.26 of bromine were added at 10° C. to a solution of 1.88 g of diphenyldiselenium and 6 ml of THF. The reaction mixture was stirred for 1 hour at 20° C.
c) Reaction
A mixture of 3.44 g of 1,2-dimethylethyl (1S-cis) 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino [1,2-a]-1,2-diazepine-1-carboxylate was cooled at −65° C. and the solution of LDA prepared above was added. The reaction mixture was stirred for 10 minutes and the solution of C6H5SeBr was added at a temperature of 60° C. +5° C. The temperature was allowed to return to about 0° C. and 4 ml of water, 1.2 of ml of acetic acid and 4 ml of hydrogen peroxide were added. The temperature was allowed to rise to 10° C. and the reaction mixture was stirred for 1 hour. Then, 40 ml of a 10% aqueous solution of sodium chloride and 80 ml of ethyl acetate were added. The reaction mixture was decanted, washed with a saturated solution of sodium chloride, and/or sodium bicarbonate at 10%, followed by evaporation under reduced pressure. The resultant mixture was chromatographed on silica, eluting with a methylene chloride-isopropyl ether mixture to obtain 1.3 g of the desired product with a specific rotation of αD=+126.5° C. =0.335/MeOH
Use: 1,1-dimethylethyl (1S-cis) 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2-diazepine-1-carboxylate.
a) Preparation of the catalyst
A mixture of 0.106 g of Raney nickel (Jansen) and 2 ml of sodium hydroxide was stirred for 2 hours at 60° C. and the nickel was washed with water. One drop of acetic acid was added to the last wash water and the nickel was then washed with ethanol and ethyl acetate. The nickel obtained was kept under reduced pressure.
b) Reduction
3 ml of ethyl acetate were added to 0.053 g of nickel prepared as previously and 0.0485 g of the product of Example 1 was added to the suspension obtained. The hydrogenation stage took place at ambient temperature, until there was no further absorption of hydrogen. 2 ml of hydrogen were absorbed and the product had a TLC rf=0.27 eluant isopropyl ether/methylene chloride (50-50).
Various modifications of the products and processes of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims.
Claims (11)
1. A compound of the formula 
wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the amine is free or protected.
2. A compound of claim 1 of the formula 
wherein R is defined as in claim 1, R2 is hydrogen and R1 is selected from the group consisting of 
Ra, Rb, Rc and Rd are individually selected from the group consisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbon atoms and mono- or polycyclic containing at least one heteroatom and X is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R1 and R2 together with the nitrogen to which they are attached form a mono- or polycyclic with at least one heteroatom.
3. A compound of claim 2 wherein R1 and R2 together with the nitrogen to which they are attached form a polycyclic containing at least one heteroatom.
4. A compound of claim 3 of the formula 
wherein R is alkyl of 1 to 8 carbon atoms.
5. A compound of claim 1 wherein R is 1,1-dimethylethyl.
6. A compound of claim 1 which is 1,1-dimethylethyl (9S), 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino [1,2-a]-diazepine-1-carboxylate.
7. A process for the preparation of a compound of claim 1 wherein R has the definition of claim 1 and the amine is protected comprising reacting a compound of the formula 
wherein R has the definition of claim 1 and the amine is protected with a dehydrogenation agent.
8. The process of claim 7 wherein the starting compound has the formula 
wherein R is defined, as in claim 1, R2 is hydrogen and R1 is selected from the group consisting of 
Ra, Rb, Rc and Rd are individually selected from the group consisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbon atoms and mono- or polycyclic containing at least one heteroatom and X is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R1 and R2 together with the nitrogen to which they are attached form a mono- or polycyclic with at least one heteroatom.
9. A process for the preparation of a compound of the formula 
wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the amine is optionally protected comprising reacting a compound of claim 1 with a reducing agent.
10. The process of claim 9 wherein the reducing agent is hydrogen in the presence of Raney nickel.
11. A process for the preparation of a compound of the formula 
wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms, R2 is hydrogen and R1 is selected from the group consisting of 
Ra, Rb, Rc and Rd are individually selected from the group consisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbon atoms and mono- or polycyclic containing at least one heteroatom and X is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R1 and R2 together with the nitrogen to which they are attached form a mono- or polycyclic with at least one heteroatom comprising reacting a compound of claim 2 with a reducing agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/765,761 US6433164B2 (en) | 1998-04-27 | 2001-01-19 | (3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic-acid derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9805242 | 1998-04-27 | ||
| FR9805242A FR2777888B1 (en) | 1998-04-27 | 1998-04-27 | NOVEL DERIVATIVES OF ACID (3,4,7,8,9,10-HEXAHYDRO-6,10- DIOXO-6H-PYRIDAZINO [1,2-A] [1,2] DIAZEPINE-1-CARBOXYLIC, THEIR PROCESS OF PREPARATION AND THEIR APPLICATION TO THE PREPARATION OF MEDICINES |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/765,761 Continuation US6433164B2 (en) | 1998-04-27 | 2001-01-19 | (3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic-acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US6258947B1 true US6258947B1 (en) | 2001-07-10 |
Family
ID=9525704
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/296,325 Expired - Lifetime US6258947B1 (en) | 1998-04-27 | 1999-04-22 | (3,4,7,8,9,10-hexahydro-6,10-dioxo-6H pyridazino[1,2-A] [1,2] diazepine-1-carboxylic acid derivatives |
| US09/765,761 Expired - Lifetime US6433164B2 (en) | 1998-04-27 | 2001-01-19 | (3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic-acid derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/765,761 Expired - Lifetime US6433164B2 (en) | 1998-04-27 | 2001-01-19 | (3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic-acid derivatives |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US6258947B1 (en) |
| EP (1) | EP0955310B1 (en) |
| JP (1) | JP2000001489A (en) |
| AT (1) | ATE279434T1 (en) |
| DE (1) | DE69921011T2 (en) |
| DK (1) | DK0955310T3 (en) |
| ES (1) | ES2229641T3 (en) |
| FR (1) | FR2777888B1 (en) |
| PT (1) | PT955310E (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040047978A1 (en) * | 2000-08-04 | 2004-03-11 | Hossainy Syed F.A. | Composition for coating an implantable prosthesis |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6177565B1 (en) | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
| US6201118B1 (en) | 1998-08-19 | 2001-03-13 | Vertex Pharmaceuticals Inc. | Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4512924A (en) | 1982-05-12 | 1985-04-23 | Hoffmann-La Roche Inc. | Pyridazo[1,2-a][1,2]diazepines |
| EP0570764A2 (en) | 1992-05-18 | 1993-11-24 | F.Hoffmann-La Roche & Co. Aktiengesellschaft | Asymmetric hydrogenation |
| WO1997022619A2 (en) | 1995-12-20 | 1997-06-26 | Vertex Pharmaceuticals Incorporated | INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME |
| US5723602A (en) | 1992-05-18 | 1998-03-03 | E. R. Squibb & Sons, Inc. | Dual action inhibitors containing a pyridazinodiazepine or pyrazolodiazepine lactam ring |
-
1998
- 1998-04-27 FR FR9805242A patent/FR2777888B1/en not_active Expired - Lifetime
-
1999
- 1999-04-13 JP JP11105457A patent/JP2000001489A/en active Pending
- 1999-04-22 US US09/296,325 patent/US6258947B1/en not_active Expired - Lifetime
- 1999-04-26 DK DK99401019T patent/DK0955310T3/en active
- 1999-04-26 PT PT99401019T patent/PT955310E/en unknown
- 1999-04-26 ES ES99401019T patent/ES2229641T3/en not_active Expired - Lifetime
- 1999-04-26 EP EP99401019A patent/EP0955310B1/en not_active Expired - Lifetime
- 1999-04-26 AT AT99401019T patent/ATE279434T1/en active
- 1999-04-26 DE DE69921011T patent/DE69921011T2/en not_active Expired - Lifetime
-
2001
- 2001-01-19 US US09/765,761 patent/US6433164B2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4512924A (en) | 1982-05-12 | 1985-04-23 | Hoffmann-La Roche Inc. | Pyridazo[1,2-a][1,2]diazepines |
| EP0570764A2 (en) | 1992-05-18 | 1993-11-24 | F.Hoffmann-La Roche & Co. Aktiengesellschaft | Asymmetric hydrogenation |
| US5723602A (en) | 1992-05-18 | 1998-03-03 | E. R. Squibb & Sons, Inc. | Dual action inhibitors containing a pyridazinodiazepine or pyrazolodiazepine lactam ring |
| WO1997022619A2 (en) | 1995-12-20 | 1997-06-26 | Vertex Pharmaceuticals Incorporated | INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME |
Non-Patent Citations (1)
| Title |
|---|
| CAS printout of Abstrat and structures of WO 97/22619, Oct. 1997. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040047978A1 (en) * | 2000-08-04 | 2004-03-11 | Hossainy Syed F.A. | Composition for coating an implantable prosthesis |
Also Published As
| Publication number | Publication date |
|---|---|
| PT955310E (en) | 2005-01-31 |
| EP0955310B1 (en) | 2004-10-13 |
| FR2777888A1 (en) | 1999-10-29 |
| EP0955310A1 (en) | 1999-11-10 |
| US6433164B2 (en) | 2002-08-13 |
| ES2229641T3 (en) | 2005-04-16 |
| DK0955310T3 (en) | 2005-02-14 |
| ATE279434T1 (en) | 2004-10-15 |
| FR2777888B1 (en) | 2004-07-16 |
| JP2000001489A (en) | 2000-01-07 |
| DE69921011D1 (en) | 2004-11-18 |
| US20010002422A1 (en) | 2001-05-31 |
| DE69921011T2 (en) | 2005-10-27 |
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